PROJECTSUMMARY Thisapplicationentitled,?Asmallmoleculep75NTRligandtotreatpost-strokemixeddementia?,isinresponseto NIAExploratory/DevelopmentalResearchGrantProgram(ParentR21;?PA-18-489). Mixed dementia is a complex form of dementia in which heterogeneous disease states co-exist, the most commonbeingpathologiccharacteristicsofvasculardementia(VaD),suchaschronicstrokeinfarcts,alongside pathologic characteristics of Alzheimer?s disease (AD). It is unknown precisely how many patients presently diagnosed with a particular type of dementia actually have mixed dementia, however post-mortem analyses suggestthattheconditionmaybepresentinnearly50%ofpatientsclinicallydiagnosedwithAD.Yetdespitethe frequentco-existenceofVaDandAD,littleisknownabouthowthesediseasesinfluenceeachother,inpartdue tothelackofadequateanimalmodelsofmixeddementia,andtherearenoprovendiseasemodifyingtherapies. Toaddressthisneed,thegoalofthisproposalistotestifafirst-in-classsmallmolecule,orallybioavailablep75 neurotrophin receptor (p75NTR) ligand, LM11A-31, currently in Phase IIa clinical trials for the treatment of AD, alsohasefficacyintwodifferentmousemodelsofpost-strokemixeddementia.Thefirst,isaninnovativemodel ofpost-strokemixeddementiainwhichintheweeksfollowingstroke,agedwildtype(wt)miceexhibitcholinergic neurodegeneration along with the appearance of neuritic plaques resembling those found in AD (Aim 1). The second, is a transgenic mouse model of mixed dementia in which aged Ab?PPL/Smice that have undergone a strokedevelopmoresevereADpathologythantheirage-matchedcounterparts(Aim2).Inbothofthesemodels, micealsodevelopdelayedcognitiveimpairmentsintheweeksafterstroke.Positiveresultsobtainedherewould be the first validation that p75NTR is an effective therapeutic target in two post-stroke mixed dementia models, andcouldfast-trackLM11A-31intopost-strokemixeddementiaclinicaltesting.